1. Field of the Invention
The invention pertains to bone grafting material, bone graft articles and compositions, and methods of enhancing healing or desired tissue growth by adding Melatonin to bone grafts, implants, and tissue engineering scaffolds.
2. Description of Related Art
Melatonin is a well known hormone, best known to lay persons and others as an over-the-counter oral supplement useful in combating jet lag and insomnia. Melatonin, chemically known as N-acetyl-5-methoxytryptamine, is a naturally-occurring compound found in animals, plants, and various microorganisms. In humans and animals, Melatonin production and circulating blood levels vary, and govern, a number of biological functions in a daily circadian rhythm including but not limited to sleep cycles. While much is known about Melatonin, it is most often thought of even among health care providers as a circadian regulator, an antioxidant, and for suspected efficacy in (without limitation): cancer prevention and treatment; prevention or treatment of ischemic or cardiovascular disease; treatment of Attention Deficit Hyperactivity Disorder; reduction of incidence of infertility; reduction of occurrence or severity of headaches; treatment of mood disorders, reduction of gall bladder stones, and treatment of Amyotrophic Lateral Sclerosis.
Prior to the present invention discussed below, minimal if any attention has been given to the ability of in situ Melatonin to enhance bone healing in a bone implant or graft scenario, or to enhance tissue growth on a tissue engineering scaffold. Instead, bone healing has heretofore been a medical art in which various materials and substances have been used to enhance bone healing with or without bone grafts of various types, as described below.
There are approximately 500,000 joint replacement and bone graft surgeries annually in the United States and 2.2 million bone surgeries annually worldwide, making bone the second most commonly transplanted tissue (skin is the first most commonly transplanted tissue). The two most common methods of bone replacement are the autograft and the allograft, which together make up about 90% of the bone grafts used overall. Autologous bone grafts (autografts) involve selecting and moving a portion of a patient's own bone to serve as a bone graft, such as in patients requiring extensive jaw reconstruction whose jaw bones are grafted from bone shavings taken from the patients' own hip bone. Allografts may be made from exogenous human bone—generally cadaverous bone from a bone bank rather than bone donated from a donor, and xenografts (such as bovine bone) are typically highly engineered before use and are often distributed as simple calcified matrices.
The use of synthetic materials rather than human or animal based grafts can eliminate disease transmission and provide larger implants or scaffolds than is otherwise feasible. Artificial or synthetic bone graft materials include without limitation metal replacements, ceramics such as calcium phosphates (e.g. hydroxyapatite and tricalcium phosphate), BioGlass® brand of bioactive glass containing SiO2, Na2O, CaO and P2O5, and those based on calcium sulfate, all of which are biologically active to different degrees depending on their individual solubilities in the physiological environment. Synthetic scaffolds and bone graft materials in recent times have made up only about 10% of all bone graft materials used. Synthetic scaffolds strive to meet several criteria: osteoconductivity; osteoinductivity; osteogenicity; and good osteointegration. Challenges in meeting these criteria center around the need for materials which are strong but not brittle while being nonetheless adequately porous to allow solid integration of the adjacent growing and healing bone.
Most bone graft materials may be crafted as a solid construct for insertion, or as a powder for pouring, into bone voids or bone wounds of many kinds. Such voids or wounds include, without limitation, dramatic reconstructions such as those that are needed in combat situations, as well as everyday bone voids that occur in mandibular or maxillary bone after tooth extractions. Comparatively recently, calcium aluminate based bone graft and implant materials have attracted increasing attention in bone repair and healing.
A prior art published patent application of interest is U.S. Published Patent Application No. 20070224678, entitled “Functionalized Artificial Bone and Joint Compositions and Methods of Use and Manufacture,” published on Sep. 27, 2007. In this Published Patent Application (hereinafter “678”), the specification identifies certain functionalizations of calcium aluminate compositions by affixing a linking agent thereto, which linking agent is then used to link a biologically active agent such as an antibiotic (ampicillin for example), a peptide, or other active agent to the calcium aluminate substrate surface.
From a commercial standpoint, artificial or synthetic bone graft materials are arguably preferable to auto-, allo- and xeno-graft materials. However, some prior art artificial bone graft materials, such as calcium phosphate based materials, are excessively brittle to permit good results, because the three-dimensional scaffolds made from these brittle materials cannot avoid cracking or breaking upon implantation. Other synthetic bone graft materials, such as the calcium aluminate based compositions, both unhydrated and hydrated, are not excessively brittle and can provide a much better bone graft and bone implant scaffold than certain other ceramic or glass materials. Heretofore both calcium- and non-calcium based materials, including titanium and stainless steel bone replacement joints, have often been plagued by unwanted effects such as formation of excessive scar tissue adjacent to an implant. Scar tissue formation adjacent an implanted surface interferes with the interface between the implant and the bone and prevents the ultimate successful joining of bone to implant or graft. Indeed, some hip replacement surgeries result in the formation of so much scar tissue between the new joint and the adjacent bone that the surgery must actually be repeated to remove and replace the implant(s) altogether. Even the acknowledged very good artificial bone compositions according to U.S. Published Patent Application No. 20070224678 can allow an unacceptable amount of scar tissue to form adjacent the materials in vivo, with fibroblast formation being indicative of, and the predominant substituent of, this unwanted scar tissue. A need thus remains for a vastly improved bone graft, bone implant scaffold and healing enhancement material, able to accomplish all of: a) greatly improved bone wound healing; b) suppression of fibroblast growth and scar tissue formation; and c) good physical property characteristics for grafting or implantation (strength without brittleness). In addition, ideally such a material will be able to be formed or molded at room temperature with simple equipment, to enhance bone grafting and wound healing in the most difficult surgical environments of combat or disaster response areas as well as in everyday hospital procedures.